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ASH 2024 | Annualized bleeding rates in patients with hemophilia A/B and inhibitors treated with concizumab
Amy Shapiro, MD, Indiana University Hemophilia Center, Indianapolis, IN, presents the results of the Phase III explorer7 clinical trial (NCT04083781), which evaluated the efficacy of concizumab prophylaxis in patients with hemophilia A and B with inhibitors with or without target joints at baseline. Dr Shapiro highlights that concizumab prophylaxis was well-tolerated and significantly reduced annualized bleeding rates (ABR) at the 32-week cutoff, irrespective of the presence of target joints at baseline. This benefit was maintained at the 56-week time point. This interview took place at the 66th ASH Annual Meeting and Exposition, held in San Diego, CA.
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Transcript (AI-generated)
So the first study is the annualized bleeding rates in patients with hemophilia A and B with inhibitors with and without target joints at baseline in the concizumab Phase III explorer7 trial. Concizumab is an anti-TFPI monoclonal antibody directed against the Kunitz II domain and it’s administered as a once-daily subcutaneous injection. It decreases TFPI inhibition of 10A, allowing tissue factor 7A complex to produce more factor 10A and increasing thrombin generation...
So the first study is the annualized bleeding rates in patients with hemophilia A and B with inhibitors with and without target joints at baseline in the concizumab Phase III explorer7 trial. Concizumab is an anti-TFPI monoclonal antibody directed against the Kunitz II domain and it’s administered as a once-daily subcutaneous injection. It decreases TFPI inhibition of 10A, allowing tissue factor 7A complex to produce more factor 10A and increasing thrombin generation.
The explorer7 study had four arms. Arms 1 and 2 were randomized, 1:2, to initial treatment for bleeds with standard therapy, which was arm 1 or on-demand, versus start of concizumab prophylaxis, which is arm two. Arm one treated for 24 weeks, and after which they were given the option to change to concizumab prophylaxis, and arm two continued on concizumab prophylaxis as the patients desired. Arms three and four were treated with concizumab prophylaxis. The data cutoffs were 32 weeks and 56 weeks. The primary endpoint was the number of treated spontaneous and traumatic bleeding events as assessed at 32 weeks and at 56 weeks.
133 patients were enrolled. 80 had hemophilia A with an inhibitor and 53 had hemophilia B with an inhibitor – that’s quite a large number of hemophilia B patients with an inhibitor and represents approximately 14 percent of the number reported by the world federation of hemophilia.
The aim for this analysis was to assess the annualized bleeding rate in patients with hemophilia A and B with inhibitors with or without target joints at baseline. A target joint was defined as a joint with greater than or equal to three spontaneous bleeds into a single joint within a consecutive six-month period. Target joints were deemed resolved when this was less than or equal to two bleeds within a 12-month consecutive period.
Comparing patients with target joints in arm one, which was 10 patients, to arm two, which was 15 patients, the estimated ABR was decreased from 10.6 for the on-demand treatment to 1.7 on the concizumab prophylaxis, which equals an 84% reduction in ABR. For those without a target joint in arm one, which was nine patients versus arm two 18 patients the ABR was reduced from nine to 0.9 – a 90 percent reduction. The number of patients with zero treated bleeds was also higher or improved in the concizumab arm for both patients with baseline target joint which went from 20 to 53 percent zero treated bleeds so increased number of patients without bleeding episodes and those without a target joint 67 to 94 percent. The median ABR for treated spontaneous and traumatic target joint bleeds in patients who switched in arm one from their on-demand treatment to concizumab prophylaxis was zero at 56 weeks.
Specifically for those patients with a target joint, the median ABR was 1.9 versus zero for those starting on concizumab prophylaxis. For those without a target joint, the median ABR was zero in both groups. The median ABR for treated spontaneous and traumatic target joints for arms two through four was zero, regardless of target joints at baseline at 32 and 56 weeks.
The safety data at 56 weeks showed no new findings. The study conclusions for this analysis were that once daily subcutaneous concizumab prophylaxis effectively reduced ABR, irrespective of the presence of target joints at baseline at the 32-week cutoff. The low ABRs with concizumab prophylaxis were maintained at 56 weeks, and that concizumab prophylaxis showed a favorable safety profile and was well-tolerated in patients with hemophilia A and B with inhibitors.
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Disclosures
Plasminogen Deficiency Foundation: Membership on an entity’s Board of Directors or advisory committees; Regeneron: Research Funding; Sanofi-Genzyme/Bioverativ: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hema Biologics: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Kedrion Biopharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda Pharmaceuticals: Research Funding; Pharmacosmos A/S: Research Funding; Cantessa Pharmaceuticals/ApcinteX Ltd.: Research Funding; Novo Nordisk Haemophilia Foundation: Membership on an entity’s Board of Directors or advisory committees; Be Biopharma: Membership on an entity’s Board of Directors or advisory committees; Genentech/Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Indiana Hemophilia & Thrombosis Center, Inc.: Current Employment; BioMarin: Membership on an entity’s Board of Directors or advisory committees; NHPCC: Other: Medical Director.
